This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 119/6/788    most recent CIRCULATIONAHA.108.817379v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Joung, B. Articles by Lin, S.-F. Search for Related Content PubMed PubMed Citation Articles by Joung, B. Articles by Lin, S.-F. Related Collections Animal models of human disease Arrythmias-basic studies Calcium cycling/excitation-contraction coupling Related Article

(Circulation. 2009;119:788-796.)
© 2009 American Heart Association, Inc.

Arrhythmia/Electrophysiology

Intracellular Calcium Dynamics and Acceleration of Sinus Rhythm by β-Adrenergic Stimulation

Boyoung Joung, MD, PhD; Liang Tang, PhD; Mitsunori Maruyama, MD; Seongwook Han, MD, PhD; Zhenhui Chen, PhD; Marcelle Stucky, BS; Larry R. Jones, PhD; Michael C. Fishbein, MD; James N. Weiss, MD; Peng-Sheng Chen, MD; Shien-Fong Lin, PhD

From the Krannert Institute of Cardiology and the Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis (B.J., L.T., M.M., S.H., Z.C., M.S., L.R.J., P.C., S.L.); and Department of Pathology and Laboratory Medicine (M.C.F.) and Division of Cardiology, Department of Medicine, and Department of Physiology (J.N.W.), David Geffen School of Medicine, University of California at Los Angeles.

Correspondence to Shien-Fong Lin, PhD, 1801 N Capitol Ave, E 308, Indianapolis, IN 46202. E-mail linsf{at}iupui.edu

Received August 25, 2008; accepted December 8, 2008.

Background— Recent evidence indicates that membrane voltage and Ca²⁺ clocks jointly regulate sinoatrial node (SAN) automaticity. Here we test the hypothesis that sinus rate acceleration by β-adrenergic stimulation involves synergistic interactions between these clock mechanisms.

Methods and Results— We simultaneously mapped intracellular calcium (Ca_i) and membrane potential in 25 isolated canine right atrium, using previously described criteria of the timing of late diastolic Ca_i elevation (LDCAE) relative to the action potential upstroke to detect the Ca²⁺ clock. Before isoproterenol, the earliest pacemaking site occurred in the inferior SAN, and LDCAE was observed in only 4 of 25 preparations. Isoproterenol infusion (1 µmol/L) increased sinus rate and shifted pacemaking site to superior SAN, concomitant with the appearance of LDCAE preceding the action potential upstroke by 98±31 ms. Caffeine had similar effects, whereas sarcoplasmic reticulum Ca²⁺ depletion with ryanodine and thapsigargin prevented isoproterenol-induced LDCAE and blunted sinus rate acceleration. Ca_i transient relaxation time during isoproterenol was shorter in superior SAN (124±34 ms) than inferior SAN (138±24 ms; P=0.01) or right atrium (164±33 ms; P=0.001) and was associated with a lower sarcoplasmic reticulum Ca²⁺ ATPase pump to phospholamban protein ratio in SAN than in right atrium. Hyperpolarization-activated pacemaker current (I_f) blockade with ZD 7288 modestly blunted but did not prevent LDCAE or sinus rate acceleration by isoproterenol.

Conclusions— Acceleration of the Ca²⁺ clock in the superior SAN plays an important role in sinus acceleration during β-adrenergic stimulation, interacting synergistically with the voltage clock to increase sinus rate.

---

 

CLINICAL PERSPECTIVE

Related Article:

Clinical Summaries
Circulation 2009 119: 765-767. [Extract] [Full Text]